Therapeutic administration of effective amounts of dimethyl sulfoxide to human and animal subjects



United States Patent Office 3,549,770 Patented Dec. 22, 1970 THERAPEUTIC ADMINISTRATION OF EFFECTIVE AMOUNTS F DIMETHYL SULFOXIDE T0 HU- MAN AND ANIMAL SUBJECTS Robert J. Herschler, Camas, Wash., and Stanley W. Jacob, Oswego, Oreg., assignors, by mesne assignments, to Crown Zellerbach Corporation, San Francisco, Calif., a corporation of Nevada No Drawing. Continuation-impart of applications Ser. No. 329,238, Ser. No. 329,208, Ser. No. 329,205, Ser. No. 329,271, and Ser. No. 329,209, all filed Dec. 9, 1963; Ser. No. 346,366, and Ser. No. 417,781, Feb. 10, 1964; Ser. No. 417,788, and Ser. No. 417,797, Dec. 11, 1964. This application Nov. 28, 1967, Ser. No. 686,295

Int. Cl. A61k 27/00 US. Cl. 424--337 37 Claims ABSTRACT OF THE DISCLOSURE Effective amounts of dimethyl sulfoxide, as an essential active agent or ingredient is administered to animals topically, by injection, by instillation into body orifices and orally for ph-armacologic effects and to treat various disorders, namely, the relief of pain, the relief of tissue inflammation, the stimulation of tissue repair, the relief of the signs and symptoms of arthritis, the relief of the signs and symptoms of respiratory distress, the promotion of muscle relaxation, the relief of symptoms and promotion of healing of burns, the promotion of skin grafting, the relief of symptoms of vascular insufficiency and the relief of emotional overactivity and mental depression. Compositions and dosage forms for dimethyl sulfoxide administration are described including lotions, ointments, paints, suppositories, sprays and injectable solutions.

This is a continuation-in-part of our copending United States applications Ser. Nos. 329,238, entitled Analgesia; 329,208, entitled Relief of Tissue Inflammation and Stimulation of Repair; 329,205, entitled Relief of Signs and Symptoms of Arthritis; 329,271, entitled Relief of Signs and symptoms of Respiratory Distress; and 329,209, entitled Tranquilization, all filed Dec. 9, 1963; Ser. No. 346,366, entitled Control of Microorganisms, filed Feb. 10, 1964; and Ser. Nos. 417,781, entitled Muscle Relaxation; 417,788, entitled Treatment of Burns and Promo tion of Skin Grafts and 417,797, entitled Relieving Symptoms of Vascular Insufficiency, all filed Dec. 11, 1964, all presently now abandoned.

BACKGROUND OF THE INVENTION This invention relates to the use of dimethyl sulfoxide as a pharmaceutical (i.e., as an essential active agent or ingredient) to treat a variety of signs and symptoms as will be discussed in detail herein. For the various conditions treatable under the present invention, a considerable variety of medication and treatment exists. However, each has its limitations due to allergic response or potentially damaging side effects, restricted spectrum of activity (effective only in limited types of disorders), restricted routes of administration, lack of individual response in a certain percentage of individuals, expense, etc. Therefore, additional agents are constantly being sought which can replace, supplement, or augment existing medication.

In achieving pharmaceutical effects, it is desirable to utilize an agent which is both well tolerated and conveniently administered. In addition to the obvious advantages of patient acceptability, topical application is a particularly advantageous route where treatment of a localized condition is desired since the effect of the agent may be concentrated at the area under treatment for rapid and specific results. Relatively few pharmaceuticals may be effectively applied topically to the skin and mucous membranes of the body cavities, particularly to obtain a response in disorders involving deeper tissues, structures and organs. Thus, with most pharmaceuticals the only alternative to esthetically undesirable localized injections has been generalized systemic medication (necessarily slower acting) through oral administration. Their usefulness has therefore been severely restricted.

Many of the syndromes with which this invention is concerned have a plurality of signs and symptoms, as for example pain, inflammation and tissue damage, which require treatment. Most drugs are capable only of treatingone or possibly two of such signs and symptoms so combined therapy where more than one drug may be necessary. Since it may be desirable for increased effectiveness, economy, minimized side affects, etc., to treat as many signs and symptoms of a given disorder as possible with a single agent, agents which have the cap-ability of relieving a multiplicity of signs and symptoms frequently associated together in the same disorder are of considerable value.

Accordingly, it is desirable in the field of medicine to provide new pharmaceuticals which are favorably tolerat ed and are substantially non-toxic at effective levels of administration. It is further desirable to provide pharmaceuticals which are effective in a wide range of conditions and which may be administered conveniently and by a variety of routes, particularly topical.

The present invention has as a primary object to pro vide such a new, well-tolerated, substantially non-toxic pharmaceutical which is effective for a wide range of conditions and which may be administered by a variety of routes, including topical route. It is a further object to provide such a pharmaceutical which has the capability of simultaneously treating a multiplicity of signs and symptoms frequently associated together in the same disorder.

Dimethyl sulfoxide, originally synthesized in 1866, is a colorless liquid at room temperature which melts at about 18.5" C. and boils at about 190 C. Over the last 25 years it has been used increasingly as an industrial solvent, reaction medium and chemical reactant.v and a considerable amount of literature has developed on its properties and industrial uses. It has been investigated for toxicity in experimental animals and for several biological functions, namely, as a protectant in freeze preservation of living tissue and as a radio protestant in experimental animals at high doses injected prior to radiation of the animals. Uses have also been discovered by one of the present inventors for dimethyl sulfoxide in the agricultural field, namely in enhancing penetration of other agents into plants, in controlling plant virus and in stimulating plant metabolic functions.

Copending applications have also been filed concerning other discovered pharmaceutical properties of di methyl sulfoxide, namely Ser. No. 329,151, filed Dec. 9, 1963, relating to enhancing animal tissue penetration of physiologically active agents with dimethyl sulfoxide and Ser. No. 343,473, filed Feb. 10, 1964, relating to effecting diuresis with dimethyl sulfoxide.

SUMMARY OF THE INVENTION Quite surprisingly, in the light of the long history, extensive experimentation, study and evaluation of this compound, it has now been discovered that dimethyl sulfoxide has previously unrecognized valuable and extensive pharmaceutical activity. It has been found to be broadly useful in the treatment of damaged tissue, particularly as an anti-inflammatory agent, and as a stimulant to repair of the damaged tissue, as an analgesic agent, as a muscle relaxant, as an agent for treating vascular insufficiency and as an agent for treating mental anxiety states and depression. It additionally has particular usefulness in relieving the collective signs and symptoms of certain specific syndromes, namely, respiratory distress, arthritis and burns. Dimethyl sulfoxide is rapidly rendered systemic in the body from all normal routes of administration and, importantly, also that it may be applied topically to the intect skin or mucous membrane to achieve highly unusual rapid absorption to the affected sites in the body. Composition forms and dosages are also provided which are especially adapted to utilize the pharmaceutical activity of dimethyl sulfoxide, particularly in connection with its unique tissue penetration properties, While at the same time avoiding undue side effects.

PHARMACEUTICAL ACTIONS Dimethyl sulfoxide has a wide spectrum of utility in the treatment of various pathological conditions of animals including humans. Unlike many other medicaments it is useful in the treatment of apparently unrelated syndromes. The range of its activity and utility is such that it is not believed to be possible in the present state of medical knowledge in all instances to describe the activity utilizing classical medical definitions. Accordingly, throughout this specification applicants will define various activities, methods of treatment, pathological conditions, and the like, for purposes of this application. In so doing, applicants will attempt to follow accepted classical medical terminology. However, it will not always be possible to do so.

Dimethyl sulfoxide has been found to be useful in the treatment of tissue damage, pain, abnormal muscle contraction and vascular insufiiciency. In some disorders only one of these manifestations may appear. But frequently two or more may appear in the same disorder. In the latter instance, dimethyl sulfoxide may be useful in treatment of all such signs and symptoms present. In certain disorders, namely, arthritis, respiratory distress, and burns, dimethyl sulfoxide is particularly beneficial in treating the entire syndrome and these will be discussed under separate headings.

As will be discussed in detail at a later point, dimethyl sulfoxide is also useful in the treatment of mental disorders, including states of emotional overactivity and mental depression.

It will be understood that in all instances used herein the terms treatment and treating shall be used in the sense of abating a disorder or relieving to some extent its signs and symptoms and they shall not necessarily infer a cure although this at times may also be the result in the practice of this invention.

Following a discussion of dosages and routes of administration which applies generally to all of the abovementioned pharmaceutical uses, the use of dimethyl sulfoxide in treating each of these conditions will be discussed and illustrated by specific examples. In selecting the examples for use in the application from among the tens of thousands of examples available to establish the utility and to illustrate the use of dimethyl sulfoxide, applicants have selected almost exclusively from those examples where an objective response could be measured or observed by the individual administering the treatment. A large number of other examples have been carried out in which the measure of relief was subjective rather than objective. Reference will be made at appropriate places in the text to various of these treated conditions where evaluation of response is necessarily more subjective.

DOSAGES AND ROUTES OF ADMINISTRATION Dimethyl sulfoxide may be administered by the usual oral and injectable routes. in addition to these routes,

dimethyl sulfoxide can be effectively administered topically to the skin and mucous membranes of the various body cavities as by direct application or installation. Topical applications is of particular advantage where a local effect is desired. As discussed in detail under that heading, composition and dosage for-ms include undiluted dimethyl sulfoxide or more preferably dimethyl sulfoxide along with appropriate pharmaceutical diluents, excipients or adjuvants. In general, concentrations of dimethyl sulfoxide may vary from 1% to For topical use, however, higher concentrations of from 10% to 25% and above for application to mucous membranes and at least about 50% for dermal application are preferred. The more advantageous concentrations and composition forms for particular routes of administration will also be discussed at a later point.

The dosage and frequency of administration will be determined by the expertise of the attending practitioner who considers the nature and severity of the disorder, the area involved, the response desired or observed and the subject. Generally, as illustrated by the examples which follow, the dosage may be as low as 0.01 gram per kilogram body weight and the optimum amount anywhere from around 0.02 to 0.05 up to 1.0 gram per kilogram of body weight per day or somewhat higher in a few instances. The average individual dose may be in the neighborhood of 0.1 to 0.2 gram per kg. body weight. However, the optimum dose will depend to a considerable extent upon the type and extent of the disorder and the mode of application.

The treatment may be repeated once or twice daily, or even more frequently, until appropriate response is obtained or for the duration of the complaint. For some indications, (such as many acute situations) only one or two applications involving a few cc. of dimethyl sulfoxide may be necessary while in chronic situations a more sustained regimen for a prolonged period or follow up treatments may be called for. In any case, the optimum amount for a given disorder will depend upon the factors previously mentioned. The examples which follow will serve as a useful guide for the practitioner in determining such optimum amounts and frequency of application.

Wherever feasible it may be desirable to administer the dimethyl sulfoxide locally to the involved area to achieve maximum concentrated effect. Therefore, the topical route may be preferred. Also, local injections may achieve this concentrated effect, and preferably lower concentrations of 1% to 20% dimethyl sulfoxide are used for this purpose.

It is particularly advantageous, in cases where a localized effect is desired, to apply the dimethyl sulfoxide directly to the area involved, as by Wetting skin or mucous membrane or by injection at or near the involvement.

When a more generalized effect is desired, as in the case of widespread involvements, the route of administration is less important but topical application to a surface area rich in blood vessels (as for example on the chest, back, legs and arms) is quite convenient. Higher concentrations are preferred for topical applications, such as at least 25% and more often, at least about 50%. The dimethyl sulfoxide composition may be applied by means of a cotton swab or other soft applicator. It may be conveniently applied in the form of a spray by means of an aerosol bomb or an atomizer or in a thickening base, etc., as discussed at a later point. Desirably, at each application the surface involved is thoroughly wetted. Where large areas are to be treated, it may be desirable to immerse an entire limb, torso, or body into a dilute aqueous solution of dimethyl sulfoxide. At the lower concentrations greater volumes of dimethyl sulfoxide solutions may be administered more frequently as with bathing solutions for some purposes. Less frequent applications may be effectively made with solutions containing at least about 50% of dimethyl sulfoxide.

RELIEF OF THE SIGNS AND SYMPTOMS OF TISSUE INFLAMMATION AND PROMOTION OF TISSUE REPAIR The various types of tissue damage include traumatic tissue damage by cutting, tearing, crushing, burning and the like; various physiological types of damages such as ulceration, haematoma, and the like; infectious tissue damage such as laryngitis, conjunctivitis, pyorrhea, and the like; and others of uncertain etiology, i.e., caused by uncertain or unknown injurious stimuli which somehow involve disruption or degenerative change of normal animal tissue. All the types of tissue damage, and inflammation resulting therefrom, other than infectious tissue damage, may be characterized as being caused by non-living injurious stimuli. However, unless so qualified, or otherwise qualified, the term tissue damage and inflammation resulting therefrom are intended to comprehend all disruptive or degenerative tissue states, whatever their etiology. Among the various signs noted with tissue damage are edema or swelling, erythema or redness of the skin, tenderness to touch and, particularly in the case of chronic inflammation, formation of scar tissue and eschars. A symptom frequently reported is pain. In the treatment of tissue damage, dimethyl sulfoxide is useful in promotion of tissue regeneration following such injuries as evidenced by more rapid healing, and in some instances, suppression of scar tissue formation and diminution of scar tissue, as administered in accordance with the foregoing general principles and the following examples which are illustrative. Tissue inflammation associated with tissue injury or damage may also be treated with dimethyl sulfoxide by application, preferably locally to the involved area, to relieve the edema or swelling, erythema and tenderness. Additionally, it will be noted in the following examples that in many instances other signs and symptoms frequently associated with tissue damage, such as pain, muscle spasm, vascular insufficiency, etc., may also be relieved. Treatment of these other signs and symptoms will be considered separately under appropriate headings but it is notable that multiple pharmacologic eflect can often be obtained in the treatment of many syndromes with dimethyl sulfoxide.

Topical application of dimethyl sulfoxide to the involved skin area is particularly advantageous in the case of dermal inflammations such as for example acne, eczema, herpes simplex, herpes zoster, pimples and seborrhea.

In the case of mucous membrane involvements topical application may also be advantageous. For treatment of conjunctivitis, as for example that secondary to glaucoma, application may be preferable in the form of eye drops, such as two drops of 50% dimethyl sulfoxide in water to each eye. For inflammation of the periodontal membrane of the mouth, 50% dimethyl sulfoxide in water may be applied topically directly to the involved membrane in an amount, say of one fourth cc., three times a day until the inflammation subsides. In inflammation of the perianal region, the area may be Wetted periodically with dimethyl sulfoxide until the inflammation subsides. For less accessible regions, such as the bladder in the case of interstitial cystitis, intravesical instillation of a more dilute aqueous solution of dimethyl sulfoxide may be desired.

Topical applications of dimethyl sulfoxide is also particularly suitable for treatment of the various musculoskeletal injuries such as sprains, strains, contusions, etc., the composition being applied liberally to the cutaneous areas in proximity to the injury.

Example 1.Lessening of experimental inflammation response One tenth cc. of autoclaved Bakers yeast was injected intradermally into each of 20 guinea pigs. Ten of the animals were allocated to a test group and 100% dimethyl sulfoxide was applied over the involved area. The other ten were allocated to a control group and remained untreated. In the test group, the dimethyl sulfoxide was applied as early as 10 minutes after the yeast injection in three animals, then six hours after injection in three other animals, and 24 hours after injection in the four remaining animals of the test group. All the animals in the test group had signs of inflammation which were significantly less severe than those in the control group. These signs were the degree of redness and diameter of the inflammatory wheal. This observation was true of all the animals in the test group which were given dimethyl sulfoxide at 10 minutes, 12 hours, and 24 hours after the inflammation was induced.

Example 2.Adhesions A group of ten rats were given 3 cc. of 15% dimethyl sulfoxide intraperitoneally for three days prior to injury. A second group of ten rats were left untreated. A standard injury to the cecum was produced by clamping the cecum six times with a fine haemostat. During a 10 day period following injury, 3 cc. of 15% dimethyl sulfoxide was given to each of the rats in the test group, once each day. Ten days after injury the animals in the test group averaged less than one adhesion per animal. Animals in the control group averaged six adhesions per animal.

Example 3.--Frostbite damage A 30 year old colored male subject has frostbite on his right foot. His symptoms were pain and numbness of all toes on the anterior forefoot. Two cc. of dimethyl sulfoxide was applied topically to the involved area at strength, twice daily for one week. Each application was made in sufficient amounts so that the area was surrounded by a wet layer. With each application the pain subsided. At the end of one week, the numbness has disappeared and noticeable healing was permitted to occur.

This example not only illustrates the relief of pain and inflammation associated with tissue damage arising from frostbite, but also shows tissue recovery and regeneration. Relief of vascular insufficiency, which will be discussed at a later point, is also believed to be involved.

Example 4.Insulin haematoma A 23 year old female subject, with a history of diabetes for many years, had insulin injected subcutaneously into the anterior abdominal wall. A haematoma developed having a volume of about 1 x 1 x l cm. Dimethyl sulfoxide in 100% concentration was applied topically over the haematoma. Within one hour the swelling was observed to have disappeared. The primary response was a relief of the signs of inflammation.

Example 5.-Inflammation relief and wound regeneration in ulceration A 70 year old male white subject had a history of a non-healing arteriosclerotic ulcer over the left lateral malleolus. The subject also reported a symptom of continuous rest pain. Five cc. of dimethyl sulfoxide in 100% concentration was applied topically to relieve the pain and after 24 hours there was a marked diminution in the inflammatory reaction around the ulcer. Five cc. of dimethyl sulfoxide in 100% concentration was applied twice daily for one week. After this time, the ulcer showed definite evidence of improvement as based on the epithelialization and new granulation tissue. Application of dimethyl sulfoxide resulted in relief of pain symptoms, lessened inflammation and enhanced wound healing. Relief of the causative vascular insufficiency may also have been associated with the improvement.

Example 6.-Bunion A 43 year old female white subject had a two-day history of a bunion on her toe which was painful and inflamed. The subjects toe was soaked in 100% dimethyl sulfoxide for two minutes. One day later, the sign of swelling had disappeared as well as: other evidence of inflammation. Complete relief of discomfort occurred fifteen minutes after one application with dimethyl sulfoxide. tReapplication was not necessary.

Example 7.Inflammation with burn A 62 year old female subject had a second degree burn measuring cm. in length by 5 cm. in width, over the anterior surface of the right forearm. The lower half of this wound was contacted with 100% dimethyl sulfoxide topically. Forty-eight hours after such treatment, it was seen that there were numerous blisters in the upper portion of the burn, but the part contacted by dimethyl sulfoxide was free of blisters. Five days after treatment, the lower portion of the burn which was treated with dimethyl sulfoxide showed only minimal erythema or reddening of the skin, whereas the upper part still had blisters, erythema and edema. Seven days after application, the lower part of the burn was completely healed whereas inflammation persisted in the upper area. The foregoing example indicates relief of signs and symptoms of inflammation associated with tissue damage secondary to burn, as well as enhanced tissue regeneration in damaged tissue.

Example 8.Conjunctivitis A 26 year old male subject had a history of simple catarrhal conjunctivitis. The signs included lacrimation and a watery discharge. Into the involved eye was daily instilled two drops of 50% dimethyl sulfoxide in water. About minutes after each instillation, there was a subsidence of the lacrimation and the symptom of burning. Two days after application, there was no evidence of inflammation of the conjunctiva.

Example 9.Decubitus This condition is commonly known as bedsore and it involved a 72 year old white subject with a two weeks history of a sacral decubitus, measuring 4 x 6 x 1 cm. This was probably caused by a lower vitality of the affected tissue and prolonged pressure with maceration. Dimethyl sulfoxide in 50% solution was applied liberally, 3 cc. each time, three times daily. After two days of such application, the decubitus exhibited evidence of healing. Application for two weeks was followed by complete healing of the decubitis ulcer. It is believed that the healing was enhanced by the anti-edema or anti-inflammatory effect following application of dimethyl sulfoxide, as well as enhanced tissue repair. Relief of vascular insufficiency may also have contributed.

Example 10.Eczema This condition is an exudative inflammation of the skin with a tendency to chronicity.

A 26 year old white male subject had co-existing erythematous and papular lesions of the left medial thigh diagnosed as chronic eczema. The lesions were associated with pruritis. Dimethyl sulfoxide was applied to the involved area in a concentration of 50% in water and in a volume of 2 cc. This application was repeated four times daily for three days. Following each treatment, the itching disappeared and remained absent for about three hours. Upon examination at the end of three days the chronic inflammatory process showed marked evidence of healing as noted by epithelization over segments of the lesions.

Example 11.Glossitis This inflammation of the tongue was seen in a year old white male subject WhOSe tongue had the signs of swelling, and tenderness and a symptom of pain. The subject had an accompanying cervical adenitis or inflammation of a lymph gland in the neck. Within the subjects mouth was applied 10 cc. of dimethyl sulfoxide in water. The dimethyl sulfoxide composition was kept in contact with the swollen tender tongue for about 10 minutes. Two hours after application there was observed to be a definite diminution in the swelling component of the inflammation, and in the symptom of painful tongue. Three like applications were made that same day. At the end of 24 hours, there was a marked diminution in the chronic inflammatory response.

Example 12.Edema eyelid A 33 year old female white subject had a history of headaches every two or three years coming in clusters which were diagnosed as the histamine type with typical unilateral distribution, conjunctival injection and edema of the eye lid. One hundred percent dimethyl sulfoxide was applied topically to the eyelids, and one half hour after such application, the symptom of headache had disappeared and the sign of edema of the lid had subsided.

Example 13.Myositis This term describes a general inflammation of the muscles characterized by changes in connective tissues. It should more properly be called fibromyositis, which is a part of a more general process of fibrositis.

A 53 year old female subject had a two days history of pain in the lumbosacral area of her back. This pain was aggravated by motion and there was an additional symptom of pain upon palpation when examined. There were also signs of small tender nodules. Five cc. of dimethyl sulfoxide was applied topically over the involved area. Fifteen minutes after application there was relief of pain, and after daily applications of 5 cc. of 100% dimethyl sulfoxide for one week, the small tender fibrous nodule could no longer be palpated. The symptom of pain was relieved as Well as the sign of the presence of inflammation.

Example l4.Ear inflammation Two female subjects, ages 6 and 8, suffered from an inflammatory process of the exterior auditory canal. Two drops of 100% dimethyl sulfoxide was applied topically to the involved area. Prior to application, the tympanic membrane and canal had signs of inflammation and symptoms of pain, but 30 minutes after application these areas were seen to be less inflamed and the symptom of pain was relieved.

Example 15.Otitis A three year old greyhound was seen with otitis of the right ear accompanied by a bacterial infection. The animal was observed to carry its head down on the right and continually shake it.

Dimethyl sulfoxide at 100% concentration was inserted into the external canal of the right ear in a quantity suflicient to fill it. This was repeated twice for three days. During this period the infection and inflammation were observed to subside and the animals behavior returned to normal.

Example 16.-Acne The common type of acne is a chronic inflammatory disturbance of the pilosebaceous apparatus. It is characterized by excessive oiliness of the skin, comedones, pustules, and cystic lesions.

The eruption is most common on the face, but the neck, shoulders, arms, chest, and back are not infrequently affected. Examination usually reveals a variable number of comedones, infected comedones, reddish papules, and pustules, and marked oiliness.

A 14 year old male subject with acne vulgaris of the face was given 100% dimethyl sulfoxide topically with four different applications over two days. A control area was maintained. Sufficient dimethyl sulfoxide was given in each application to wet the area to be treated. After this two-day period, a marked subsidence of the inflammatory reaction was seen in the treated area and none in the control area.

9 Example l7.Acne

Dimethyl sulfoxide is an excellent solvent for sulfur dioxide which is a gas at room temperature. Dimethyl sulfoxide containing 0.5% sulfur dioxide by weight dissolved therein was applied to one small patch of a 17 year old white females left forehead. About 0.5 cc. of the composition was applied once daily for three days. The treatment was associated with exfoliation and significant reduction in the acne condition in the treated area.

Example l8.Acne

A 14 year old male subject was examined. He showed a typical facial eruption, extending down onto the neck, characterized by comedones (infected), reddish papules, and pustules, and a marked oiliness of the skin. Treat- -ment consisted of dietary control, plus the application of a few cc. 50% dimethyl sulfoxide to the involved areas daily for one week. At the end of this time, there was a marked subsidence of the local inflammatory response. The patient continued to show improvement. At the next examination three months following the initial treatment his skin was clear.

Example l9.-Acne A 15 year old male subject was examined with a characteristic acne vulgaris eruption on his face. This subject was treated with dietary control plus 75% dimethyl sulfoxide with water, 4 cc. at each administration to the involved areas daily for a four day period. At the end of this time there was a marked subsidence of the chronic inflammatory response. The local dermatosis recurred in one week. This was retreated for four successive days. Following the second treatment, the subjects skin was relatively clear and at the time of last examination two months following the second application, his skin remained clear.

Example 20.-Acne A 15 year old female subject was examined with a two years history of acne vulgaris characterized by comedones, reddish papules, and marked oiliness of the skin of her face, neck, shoulders, upper arms, upper chest, and upper back. This subject had been relatively refractory to most conventional forms of therapy. She was treated with 100% dimethyl sulfoxide, a total of cc. daily, to the involved areas each evening for ten days. At the end of this time her skin was relatively free of this chronic inflammatory process. When last examined six weeks following the initial therapy, she was at that point still free of the signs of acne.

Example 21.Pharyngitis A 39 year old male subject had mild pharyngitis. There was no associated complaints. Five percent dimethyl sulfoxide in warm water was used as a gargle. Pronounced pain relief was reported in about 5 minutes. The subject gargled again after one hour. Examination after 2 hours showed a marked diminution of the local inflammatory reaction.

Example 22.-Seborrhea A 32 year old female subject was seen with the moist form of seborrheic dermatitis of both axillae. Examination revealed a typical eczematoid reaction. This subject was treated with 5 cc. of 50% dimethyl sulfoxide daily to the involved areas for one week. At the end of that time the evidence of her moist eczematoid chronic inflammatory pathology in both axillary areas had markedly diminished. When examined for the last time one month following initial treatment she was still asymptomatic.

Example 23.Seborrhea A 22 year old male subject with a 5 years history of severe seborrheic dermatitis was examined. He showed the typical features of dermatitis of the scalp. Twenty-five percent of dimethyl sulfoxide in water was applied four 10 times daily for two days; each time with a total dose of 5 cc. of 25% solution. At the end of two days, there was a marked diminution in the chronic inflammatory process. The benefit lasted for one month.

Example 24.Seborrhea 28 year old female subject was seen with seborrheic dermatitis of the scalp. Thirty percent dimethyl sulfoxide in water with a lotion base was applied in four cc. volume three times daily for three days. At the end of one week, all local evidence of the dandruff was gone. The benefit in this chronic inflammation lasted for three weeks; the subject was treated at that time for recurrence, again with three days treatment with the same schedule as the first treatment. This time the benefit lasted for two months.

RELIEF OF PAIN Pain also is often associated with all of the tissue injury states mentioned previously. Additionally, it may be associated with other syndromes, such as migraine headaches, phantom pain of amputees, tic douloureux, atypical facial pain, diabetic or other neuritis, etc., where there may be no apparent inflammation or tissue damage manifested. Dimethyl sulfoxide may be administered in order to diminish or relieve such pain. Preferably it is applied directly to the involved area for maximum efiect. This is particularly applicable to dermal and mucous membrane involvements. In the case of anal involvements such as pruritis ani, the dimethyl sulfoxide may be topically applied to the perianal region, liberally wetting the area periodically with the composition, to relieve the itching. The same may be practiced for itching of other mild pain resulting from a variety of causes, such as neurodermatitis of interdigital surfaces, epidermophytosis, psoriasis, herpatic neuralgia, incisional pain in minor operations as for example, in draining infected sabaceous cysts, etc. Some benefit may be obtained in the case of deeper involvements of the oral cavity such as carious lesions and lesions of the tongue, by liberally painting the mucous membranes adjacent to the involvement with the dimethyl sulfoxide composition.

In the case of pain associated with muscles, such as muscle cramps, strains or aches, the dimethyl sulfoxide may be applied topically to liberally wet the skin in proximity to the involved muscles. For pharyngitis or hiccups a concentrated composition of dimethyl sulfoxide may be painted over the entire neck region or the subject may gargle with a more dilute aqueous solution, say containing 1% by weight or preferably 10% of dimethyl sulfoxide.

In the case of headaches, a concentrated composition of dimethyl sulfoxide may be applied topically to the forehead or other head regions or a more dilute composition, say 50% aqueous dimethyl sulfoxide, may be inserted into the nostrils.

The following examples also illustrate the use of dimethyl sulfoxide to relieve pain. Again it will be noted that in many instances other signs and symptoms of the disorder treated are also relieved.

Example 25.In vitro nerve block Isolated peripheral cutaneous nerves, the saphenous nerve of cats, were set up under conventional experimental conditions and stimulated with electrodes to measure impulse conduction. With a given stimulus, local and reversible blockade of the impulse conduction occurs when dimethyl sulfoxide is applied in concentrations ranging from 25% to The nerve blockade occurs with fibers which convey impulses productive of the pain sense. When similar concentrations of dimethyl sulfoxide are applied to the fibers which convey impulses productive of touch and pressure sensations, the fibers remain functional for aperiod which is significantly longer than the period occurring with pain-producing fibers. This example illustrates that on the isolated nerve, dimethyl sulfoxide selectively blocks fibers related to pain. The demonstrated blockade considered together with the penetration of dimethyl sulfoxide through intact skin may provide a physiologic basis for pain relief through the blockage of intracutaneous and subcutaneous afferent fibers related to pain. While this may provide a partial explanation to the analgesic activity of dimethyl sulfoxide, the nature of its activity is quite analogous to that of the salicylates so a direct effect on the central nervous system may well be involved.

Example 26.-Scald burns Full thickness scald burns were made on the backs of twenty rats under ether anesthesia. The area of the scald burns was about 3 cm. wide by 8 cm. long. To a group of ten rats, a 50% dimethyl sulfoxide water solution was applied over the burned area. The other group of ten animals was retained as controls. All of the rats in the test group had a definite reduction in discomfort as compared to the controls, and this reduction occurred within ten minutes after application. It was also noticed that the characteristic edema and redness of scald burns in rats was diminished in the test group as compared with the control group. It was additionally noted that the survival time for the animals treated with dimethyl sulfoxide averaged 72 hours whereas the average survival time for controls averaged 24 hours. The basis for prolonged survival was believed to be absence of the sequelae of severe pain such as would occur in wound shock.

Example 27.Skin abrasion Three female subjects, ages five through eight, suffered skin abrasions which resulted in localized irritation. The abrasions were treated by applying 15% dimethyl sulfoxide solution in isotonic saline. The initial response after about thirty seconds was a mild burning sensation. This was followed by gradual decrease in pain symptoms, and at the end of a five minute period all three subjects reported freedom from pain. There was no recurrence of pain in any subject.

Example 28.Ankle sprain A male subject of thirty-one years suffered a severe sprain to the ligaments of the left ankle. This was followed by pronounced swelling and pain as indicated by an observed inability to walk without limping. Eight cc. of dimethyl sulfoxide was applied topically in 100% concentration to the ankle showing swelling. Within fifteen minutes the subject noted a marked decrease in pain. At the end of one hour the subject was seen to walk normally and the subjected reported to be pain free. The inflammation was also observed to be substantially decreased.

Example 29.Equine bucked shin A two year old male horse with an acute shin buck of bore forelegs was seen. This condition involves periostitis of the anterior surface of the large metacarpal or metatarsal bone and it frequently is the result of concussion occurring during exercise. The anterior surface of the metacarpal bones were swollen and tender to palpation and the horse refused to stand on its legs. 100% dimethyl sulfoxide was liberally applied by brush to the shin area of both forelegs, approximately half an ounce to each. The treated areas were then placed under bandage.

Observation of the treated animal forty minutes following treatment indicated a significant reduction in pain and inflammation. Swelling had diminished and the injured area was less sensitive to palpation. Pain relief was further evidenced by the ability of the animal to stand and walk after this short interval following treatment. Treatment was continued once daily for three days and the horse put to workout without recurrence.

Example 30.Bursitis A fifty year old male subject having a six week history of right subdeltoid bursitis was seen which resulted in limitation of shoulder motion in all directions. 100% dimethyl sulfoxide was applied topically over the right shoulder in liberal amounts so that the area remained wet. Within onehalf hour, the patient was observed to be able to move through a full range of motion without pain, and this benefit lasted six hours. 100% dimethyl sulfoxide was reapplied which resulted in painless movement for three days. A third application of 100% dimethyl sulfoxide was followed by full range motion without pain for two months.

Example 31.Stitf neck A 40 year old male subject with stiff neck had limitation of neck movements in all directions. Examination revealed marked spasm of the trapezius muscle bilaterally. Dimethyl sulfoxide at 100% strength was applied topically over both trapezius muscles. Within 20 minutes the pappable spasm had disappeared and the patient was able to move his neck in all directions without pain.

MUSCLE RELAXATION Muscle tissue is physiologically unique in that it has the ability, under normal conditions, to contact and relax via normal nerve stimuli. It is physiologically abnormal for muscle to be unable to assume a state of relaxation. This situation, however, occurs frequently. Generally it is associated with such abnormal conditions as injury, specific and non-specific infiammations, alterations of body metabolism and certain disease states. The same causative factors may result in abnormal periodic muscular contractions, i.e. spasms.

These situations, which may be referred to collectively herein as abnormal muscle contraction, may be treated effectively by administrations of dimethyl sulfoxide to induce muscle relaxation and minimize muscle spasm.

Illustrative of abnormal muscle contractions usually associated with abnormal metabolic states which may be treated are rigidity of the skeletal musculature, muscular cramps including night cramps and dysmenorrhea, and muscular tensions associated with headaches, general fatigue and occupational stress.

Illustrative of abnormal muscle contractions associated with disease are bronchial spasm, hyperkinetic disorders such as parkinsonism (paralysis agitans), spondylitis, spastic diplegia, muscular dystrophy, scleroses associated with muscle tension and muscle spasms, for example multiple sclerosis, and cerebral palsy, muscle spasms due to arthritis and bursitis and spasticity arising from inflammation of the spinal column (e.g., poliomyelitis and poisoning such as with strychnine).

Also, other abnormal contractions of uncertain etiology may be treated effectively with dimethyl sulfoxide.

In addition to inducing relaxation in the case of abnormal muscle contractions, in accordance with this invention normal muscle contractions may be reduced where this is desirable as, for example, in the performance of surgery to minimize muscular movements which interfere with surgical procedures. Dimethyl sulfoxide may be used adavntageously in conjunction with administration of anesthetics to develop maximal relaxation during surgery in place of or along with the usual curare-type compounds or the non-nitrogenous compounds such as mephenesin.

The following examples are to illustrate treatment with a dialkyl sulfoxide to relieve muscular contractions, muscle tensions, and muscle spasms attributable to musculoskeletal injuries and inflammation. It will be noted that frequently associated pain and inflammation are also relieved.

Example BZfiSkeIetaI muscle spasm A 25 year old white male with right-sided trapezius muscle spasm was examined. His major complaint was a severe pain on movement of the head of 24 hours dura tion. On evaluation, there was definite palpable spasm. Dimethyl sulfoxide, 15 cc. at 100% strength, was applied topically over the area of spasm. Upon examination one- 1 3 half hour past application the skeletal muscle was seen to be relaxed and the spasm no longer palpable.

Example 33.Night Cramps Muscles placed in unusual positions may go into tense contractions and cause severe pain. cramps in the feet or leg occurring at night are common and are usually relieved by forcibly extending the joints so as to stretch the cramped muscles. In nocturnal cramps, pain occurs so quickly that simple ischemia would not seem to be the cause. Ischemia is a local and temporary deficiency of blood due to the contraction of a blood vessel. Such cramps differ from the cramps of arterial disease in that the pain is not brought on by exercise.

A 62 year old female with an eight-year history of recurring night cramps most prominent in the back of the leg was given 100% dimethyl sulfoxide and instructed to apply 2 cc. to her calf the next time the cramping pain occurred at night. The subject followed instructions and relief of pain occurred in five minutes. It did not reoccur that night.

This particular subject subsequently experienced night cramps about six times and each time the application of between 1 and 2 cc. of 100% dimethyl sulfoxide (a dosage of about 1 to 2 grams of dimethyl sulfoxide) was topically made to the posterior calf. Application was followed by relief of night cramps without recurrence during the night.

The following examples illustrate treatment of abnormal muscle contractions associated with disease:

Example 34.Multiple sclerosis The course of the disease is characterized by remissions and exacerbations, with a steady increase in the amount of permanent damage to the nervous system andfrequently characteristic manifestations of pyramidal tract involvement, causing spasticity. Disturbances of speech are common.

Six patients with multiple sclerosis were treated with dimethyl sulfoxide. All six were given between 30 and 60 cc. of dimethyl sulfoxide daily, by direct application to the skin of the back, chest, arms, and legs with a cotton swab for a period of two weeks. At the end of this period each patient showed definite improvement including improved bladder control, disappearance of numbness, increased clarity of speech, and relief of double vision. Additionally, in all six of the patients, areas of muscle spasm were directly treated daily by swabbing of the adjacent skin with dimethyl sulfoxide in 5 to cc. amounts. Definite relaxation of the spastic muscles could be felt within one-half hour after dimethyl sulfoxide was placed over the skin. The mechanism of benefit is not yet fully determined, but we believe it to be associated with the anti-inflammatory, healing promotion and muscle relaxant properties of dimethyl sulfoxide.

Example 35.Hyperkinetic disorders Various disturbances of certain brain centers such as the mesodiencephalic activating system of the brain stem cause muscular rigidity and may impair normal movements and the ability to speak and write. This syndrome is known as Parkinsons disease, parkinsonism, or paralysis agitans. It is caused by injury to basal ganglia and is a frequent sequel to virus-caused epidemic (lethargic) encephalitis. The symptoms include involuntary tremors and rigidity of the skeletal musculature, lack of facial expression, depressed emotional tone, and salivation.

Previous drugs for controlling these symptoms have a central nervous system activity like that of atropine and they block voluntary nerve impulses at the spinal cord. However, they generally are associated with undesirable side effects similar to those encountered for other anticholinergic drugs: dryness of the mouth, dizziness, occasional mental clouding, and drowsiness accompanied by electroencephalographic tracings resembling those in normal sleep.

Examination of a 48 year old male patient presenting a typical Parkinsons syndrome revealed a resistance to passive movement in both flexion and extension of the extremities. dimethyl sulfoxide, 15 cc. daily, was administered topically to both lower extremities for one Week. At the end of the period, examination of the lower extremities revealed a relaxation of the previously noted spasm. Additionally, the dimethyl sulfoxide was associated with relief of tremor. None of the side effects of the drugs usually employed in treating this disorder were observed. This example shows the value of dimethyl sulfoxide in the relief of muscle spasm and tremor associated with the Parkinsonian syndrome.

Example 36.Rheumatoid spondylitis The patient, a 50 year old woman with rheumatoid spondylitis, was examined. She had previously been given oral salicylates, chloroquine, and intramuscular gold. These treatments did not provide relief of pain and spasm in the muscles of the back. The patient had been under treatment for one and one-half years. All medication was stopped and only dimethyl sulfoxide applied topically, 8 cc. BID. This produced moderate relief. Then 0.6 gm. acetylsalicylic acid mixed in 4 cc. of dimethyl sulfoxide was applied to the back BID. This treatment provided more benefit than the dimethyl sulfoxide alone, both in relief of muscle spasm and pain. Salicylic acid and its derivatives, as for example salicylic acid, acetylsalicylic acid and their sodium, potassium, calcium and ammonium salts and methyl salicylate, which dissolve in or can be mixed with dimethyl sulfoxide are transported by the dimethyl sulfoxide into deep layers of the skin overlying joints with resulting muscle relaxing effect in addition to that of the dimethyl sulfoxide.

The following two examples illustrate treatment of smooth muscle disorders:

Example 37.Chronic constipation A 28 year old white woman with a four year history of multiple sclerosis was treated. Among the symptoms was a marked chronic constipation relieved by periodic suppositories and enemas. One gram per kg. of body weight of dimethyl sulfoxide (100%) was administered daily topically to the back, abdomen and extremities. Within 2 weeks the patient reported that she was able to experience spontaneous bowel movements every 24 to 48 hours.

Example 38.Diaphragmatic muscle contraction Example 39.--Petit mal epilepsy A 41 year old male with a 16 year history of epilepsy (petit mal) was seen. On dilantin, phenobarbital and mesantoin the patient experienced one attack per month. 5 ml. of dimethyl sulfoxide per week was applied in substitution for other medication. The patient experienced no convulsions for a month.

Example 40.Epilepsy A 52 year old white male with a. four year history of paralysis of the left upper extremity following a stroke was treated. Periodic episodes of petit mal epilepsy ensued immediate after the stroke and recurred approximately every two weeks. Thirty m1. dimethyl sulfoxide was administered daily.

1 5 Electroencephalographic measurements of brain waves were taken 8 months before treatment, 1 week post treatment and 7 weeks post treatment. No convulsions occurred during the course of treatment:

8 months before treatment: EEG measurement abnormal.

1 week post treatment: EEG measurements approaching normal.

7 weeks post treatment: EEG measurement normal.

Example 41.Muscle relaxation in surgery The following experiment was carried out on four dogs. Two dogs were given 1 cc. of sodium pentobarbital per five pounds of body weight intravenously, the abdomen opened, and the small bowel thoroughly examined. Nembutal in this dosage range produced a significant depth of anesthesia so that adequate relaxation was obtained during examination of the small bowel and wound closure.

In two other animals, 1 cc. of Nembutal per ten pounds of body weight was given. At this dosage there was only shallow anesthesia. Since these two animals struggled at the incision, a local anesthetic (novocaine) was infiltrated into the wound and the abdomen opened. When an attempt was made to examine the small bowel, it was readily evident that insufficient relaxation was present. Dimethyl sulfoxide in sterile isotonic solution was given intravenously. The total dose administered was 2 grams per kilogram of body weight. Within a short time the combination of dimethyl sulfoxide and Nembutal permitted adequate evaluation of the small bowel with relaxation at the site of operation and a relatively easy closure of the abdomen. It is believed that, in addition to relaxing the muscles through its own activity the dimethyl sulfoxide potentiated the relaxing action of the Nembutal.

RELIEF OF SYMPTOMS OF VASCULAR INSUFFICIENCY Dimethyl sulfoxide may be administered to relieve symptoms of vascular insufficiency, and more particularly, to relieve symptoms of vascular insufliciency in vessels of the blood and lymph circulatory systems of warm blooded animals including man.

Vascular insufliciency as used herein, may be described as a disorder of a circulatory vessel resulting in the inability of the vessel to convey fluid in adequate or normal quantities. It arises from host of causes, both organic and functional.

Vascular insufliciency usually results from disorders that cause occlusion or vasoconstriction of a vessel or vessels but it may result from complete breakdown as in capillary fragility. These disorders may be primary diseases or secondary to other diseases, as for example diabetes, and, through reduced, increased or blocked flow or fluid, they are associated with many severe and damaging symptoms. Both arterial and venous diseases may result in pain, tenderness, sensory disturbances, muscle cramps, fatigue, temperature and color changes, ulceration and swelling. Arterial diseases may also lead to abnormal nail changes and atrophy. In the case of diseases involving arteries feeding the brain, partial paralysis and aphasia may result and in diseases involving the arteries feeding the heart, angina pectoris, mycocardial damage and heart failure may result. Venous diseases also may involve varicosities.

Capillary diseases result in easy bruising of the skin, hemorrhage, including nose bleeds, bleeding gums and internasal bleeding, chronic leg ulcers and, in the case of increased capillary permeability pronounced edema.

Lymphatic diseases may cause swelling, pain, fatigue, increased skin temperature, tenderness, parasthesias, muscle cramps, color changes and skin ulcerations.

Arterial vascular insufllciency due to occlusive disorders of the arteries may be due to arterial thrombosis, arteriosclerosis, collagen diseases, such as disseminated lupus erythematosus, periarterilis nodOsa, scleroderma and thromboangiitis obliterans, embolisms, arterial spasms and cold injuries, such as frost bite and chilblains, and trench foot.

Occlusive venous disorders causing vascular insufliciency include varicose veins, thrombophlebitis, phlebothrombosis and postphlebitis syndrome.

Capillary disorders causing vascular insufficiency are primarily fragility, usually secondary to infection and other disease involvement, vascular defects, toxic effect of drugs and poisons and heat reaction. Increased capillary permeability is another capillary disorder often due to irritation or inflammation. Lymphedema is the primary lymphatic disorder associated with vascular insutficiency. Lymphangitis, an inflammatory disorder also results in vascular insufliciency.

Functional disorders resulting in vascular insufficiency usually are vasconstrictor in nature. These include Raynauds disease, birth defects, shoulder girdle syndromes and post-traumatic syndromes in the case of arteries. Phlebospasm is applicable in the case of veins.

Venous and arterial disorders sometimes include involvements of the arterioles, venules and venous plexuses arteriovenous anastomoses and meta arterioles.

In arterial and venous diseases dimethyl sulfoxide may be used in accordance with this invention to relieve pain and tenderness of the affected area, sensory disturbances associated with muscle cramps and fatigue, temperature and skin color changes, ulceration, swelling, nail changes and atrophy. In disorders of the arteries feeding the brain, relief of muscular Weakness and aphasia may be obtained. In disorders of the arteries feeding the heart, pain, inflammation and tissue damage may be minimized. Varicoseveins, hemorrhoids or other varix involvements may also be treated with dimethyl sulfoxide to relieve the pain and to promote diminution in diameter of the distended vessels.

Capillary involvement may be treated with dimethyl sulfoxide to reduce edema and pain and nhance healing.

Lymphedema may be treated with dimethyl sulfoxide to reduce swelling, tenderness and pain, fatigue, paresthesias, muscle cramps, color changes and skin ulcerations.

The following example demonstrates that the response in dimethyl sulfoxide treatment of vascular insufficiency is probably at least partially due to a vasodilator effect.

Example 42.-Experimental rabbit ear Six drops of by weight dimethyl sulfoxide in water was applied topically to the prepared ear of an albino rabbit. Serial microphotographs were taken before and following application. Inspection of the photographs showed that observable vasodilation had occurred by ten minutes following application with maximal dilation at the end of twenty minutes, as indicated by a visually discernable increase in size of the blood vessels of the capillary bed in the treated area.

The following example demonstrates treatment with dimethyl sulfoxide to relieve symptoms of vascular insufficiency due to occlusive disorders in peripheral arteries.

Example 43.Arterisoc1erosis A 76 year old white male was seen with chronic occlusion of the arteries to his lower extremities. Oscillometric readings showed a 0.2 oscillation in the midleg and a 0 oscillation at the ankle. An ischemic ulcer on the medial aspect of the left ankle was present as was a great deal of rest pain. Thirty ml. of dimethyl sulfoxide was applied topically to the ulcerated area in two doses daily, 15 ml. morning and 15 ml. in the evening. At the end of two weeks there was evidence of a diminution in size of the ischemic ulcer with definite relief of rest pain.

Example 44.Arteriosclerosis obliterans A 62 year old white male was seen with a five years history of chronic occlusion (arteriosclerosis obliterans) of arteries of his lower extremities. At the time of entry,

patient had marked ischemic changes in his left foot as well as early gangrenous alterations in his left great toe. Dimethyl sulfoxide was applied. The daily dosage was 30 ml., 15 ml. in the am. and 15 ml. at night to the entire left lower extremity. At the end of two weeks there was evidence of increased Warmth and the return of normal color to the left foot. The patient was ambulated and allowed to return home. This particular individual had had intermittent claudication on two blocks prior to treatment. With dimethyl sulfoxide the two blocks intermitten claudication was extended to four blocks.

The following examples demonstrate treatment with dimethyl sulfoxide to relieve the symptoms of disorders in peripheral veins.

Example 45.Post-phlebitic syndrome A 50 year old white male was seen with a typical postphlebitic syndrome of his right lower extremity. The patient had noted an ileofemoral phlebitis four years prior to admission. Chronic edema occurred and at the time of entry the superficial veins were dilated and the medial aspect of the left ankle was pigmented and ulcerated. Prior to dimethyl sulfoxide, the patient had been treated with compression therapy. Thirty ml. dimethyl sulfoxide at 90% by weight concentration in water was applied to the right lower extremity daily over a three weeks period. After three weeks, there was a definite diminution in swelling, a reduction in the dilated superficial veins, a lessening of the pigmentation, and a reduction in size of the ulceration.

Example 46.-Equine phlebitis An 11 year old gelding with severe phlebitis at the left jugular furrow, due to improper injection of an irritating antibiotic, was seen.

Dimethyl sulfoxide at 100% was applied daily for twelve days at a dose of /2 to 2 ounces topically over the involved area. The swelling subsided rapidly contrary to the usual course of this disorder. No anticoagulants were required.

Example 47.Varicose veins A 60 year old white male was seen with primary varicose veins of both lower extremities. His presenting complaint was fatigue of the lower limbs. Dimethyl sulfoxide, 90% in water, was applied topically to the skin area adjacent to the varicose veins of the left lower extremity thoroughly wetting the area, and the right limb left untreated. Sizes of varicosities were carefully recorded. At the end of three weeks, there was a 25% reduction in the size of the varicosities of the treated limb. The veins of the untreated limb also showed a slight reduction, but this could be due to the fact that dimethyl sulfoxide was absorbed and also affected the veins of the opposite limb.

The following example demonstrates treatment with dimethyl sulfoxide to relieve the symptoms of occlusive disorders of veins serving the intestinal tract.

Example 48.-Hemorrhoids A 20 year old white male was seen with a thrombosed external hemorrhoid. Hemorrhoids are dilated veins in the area of the anus. This thrombosed hemorrhoid was painful and inflamed. Two ml. of 90% dimethyl sulfoxide in water was applied and repeated four times daily. Within 24 hours there was a marked diminution in the size of the thrombosed hemorrhoid as well as reduction in the inflammation and discomfort.

The following example demonstrates treatment with dimethyl sulfoxide to relieve the symptoms of occlusive disorders of the lymphatic systems.

Example 49.Post surgical lymphedema A 44 year old white woman who had undergone a left radical mastectomy for carcinoma was seen. In the postoperative period, severe lymphedema of the left upper extremity was observed from the tips of the fingers to the axillary area. Under ordinary circumstances this edema is prolonged and troublesome. The patient was seen three months following the operation. Thirty ml. of dimethyl sulfoxide in water daily to the left upper extremity was commenced. At the end of one month, from commencement of therapy, there was a one inch diminution in the circumference of the upper arm. The edema of the hand and wrist had disappeared completely and the patient was able to put on her wedding band and wear her watch again. This example shows the value of DMSO in the treatment of lymphedema, following lymphatic obstruction of the upper extremity.

TREATMENT OF BURNS AND PROMOTION OF SKIN GRAFTS Dimethyl sulfoxide is advantageous in the treatment of a particular traumatic tissue injury, burns, and in the promotion of skin grafts. As used herein, promotion of skin grafts is intended to mean acceleration of healing of grafts and the prevention of infection during the healing process. We have found that pain and inflammation which are involved in burns, as well as microorganism infections in the case of more severe burns, may all be beneficially treated with dimethyl sulfoxide. Additionally, treatment of burns with dimethyl sulfoxide may provide beneficial effects in addition to causing subsidence of inflammation and pain relief and not explained by these results. We find that application. of dimethyl sulfoxide may also stimulate healing and, in the case of third degree burns, cause the formation of a stable, long-term, protective covering of noninfected eschars, inhibit scar tissue, and make the damaged area more receptive to skin grafts. Thus, not only may pain and inflammation be relieved but also healing of burns may be promoted and the burned areas to a limited extent protected from infections, all through the application of a single active agent. We have found that treatment of the epithelial layer of skin preparatory to and during skin grafting with dimethyl sulfoxide may advantageously promote the formation of a rich granular layer, conducive to the taking of a skin graft, and control detrimental infections during the healing process.

In terms of severity, burns may be rated as first degree, second degree, and third degree. Where there is simple redness of the skin, the burn is termed a first degree burn. Where blisters are formed in addition to reddening of the skin, the burn is second degree. When full thickness skin damage results, the burn is termed a third degree burn. Treatment with dimethyl sulfoxide is effective with burns of all three degrees of severity. It is particularly effective in the case of third degree burns in the stimulation of healing and the promotion of noninfected eschars. The mechanism is not known at this time, but it is believed to involve promotion of tissue regeneration as well as the control of microorganisms which would otherwise hinder rapid healing.

The usual cause of burns is the exposure of body tissue to heat in some form (i.e., a thermal burn). Such burns may be the result of friction against the skin, contact with flame, hot objects or hot liquids, etc. Burns are also caused by exposure of tissue to radiant energy such as X-ray, radium, sunlight, etc. (i.e., radiation burns). Burns may also be caused by electrical discharge through tissue and by the action of corrosive chemicals in contact with tissue as, for example, vesicants (blistering agents) strong acids or strong bases. As burns of any of these origins are beneficially treated in accordance with this invention, as used herein unless specifically qualified, the term burns is intended to include tissue lesions from all of the aforementioned causes.

Desirably, treatment is commenced soon after the burn occurs. Nevertheless, application of dimethyl sulfoxide some hours or days after the burn has occurred may be useful. The dimethyl sulfoxide composition may be applied directly to the involved area by means of a cotton swab or other soft applicator. It may be desirable, in order to minimize pain and discomfort due to direct contact of an applicator on the sensitive tissue, to apply the dimethyl sulfoxide composition in the form of a spray be means of an aerosol bomb or an atomizer. Or, when large areas are to be treated, it may be desirable to immerse an entire limb, torso or body into a dilute aqueous solution of dimethyl sulfoxide. As is generally the case in treatment by irrigation of open wounds, the concentration of dimethyl sulfoxide in formulations used to treat deep second or third degree burns, particularly large open burns, desirably should be no higher than about 5 by weight and preferably 25% and lower to minimize the possibility of tissue irritation or injury. As the acute process subsides the concentration may gradually be increased. Isotonic saline solutions are particularly suitable. For such treatments dimethyl sulfoxide may be combined with the usual burn treating agents as, for example, tannic acid, boric acid, ascorbic acid, antihistamines or antibiotics.

For the promotion of skin grafts dimethyl sulfoxide is applied in the same manner, both in preparing the granulating bed for acceptance of a graft and in healing the skin graft. Desirably, where the graft is to replace skin damaged by burns, the damaged area is treated as described previously to form a noninfected eschar with a luxuriant granulating bed below it conducive to the take of the grafted skin. The eschar is removed immediately before applying the graft in the usual manner. Periodically after the graft, dimethyl sulfoxide may be applied in the above manner to stimulate healing and to prevent infections.

In nonburn graft situations, the granulating bed for receiving the graft is prepared in the usual fashion as by scraping the skin and the graft applied. Dimethyl sulfoxide may then be periodically applied to the grafted area as in the case of burn graft situations.

The following examples are illustrative.

Example 50-Third degree scald burn A 58 year old female subject had a scald burn on her left hand which was evaluated as being 50% second degree and 50% third degree. This burn was treated with a 50% dimethyl sulfoxide solution in water one-half hour after injury. Ten minutes after treatment, the subject estimated that her pain was more than half gone." Following treatment, there was a prolonged adherence of a noninfected burn eschar in the area of third degree burn. This adherence of dead tissue made it possible for the third degree burn to be effectively covered by skin without the necessity of early grafting. The subjects own noninfected, although dead, skin acted as biological covering. When the dead skin finally sloughed, the granulation bed was clear, allowing an autogenous skin graft with 100% take.

Example 51.Chemical burn (vesicant) A male subject of 40 years of age accidentally came into contact with a vesicant poison of the mustard series, which caused severe irritation to the skin of the face, neck and hands. The painful irritation was characterized by both burning and itching sensations. A 25 solution of dimethyl sulfoxide in isotonic saline was applied with a cotton applicator to the surfaces of the irritated skin. Pronounced relief was observed within five minutes, and within fifteen minutes there was essentially no sensation of irritation or discomfort. The irritated area was retreated with the 25% solution of dimethyl sulfoxide in isotonic saline every four hours for a total of three treatments, and then once a day for the succeeding two days. Healing was normal and there was no subsequent secondary infection or other complications.

Example 52.-Second degree thermal burn A 62 year old female subject had a second degree thermal burn measuring 10 cm. in length by cm. in

width, over the anterior surface of the right forearm. The lower half of this wound was contacted with dimethyl sulfoxide topically. Forty-eight hours after such treatment, it was seen that there were numerous blisters in the upper portion of the burn, but the part contacted by dimethyl sulfoxide was free of blisters. Five days after treatment, the lower portion of the burn which was treated with dimethyl sulfoxide showed only minimal erythema or reddening of the skin, whereas the upper part still had blisters, erythema and edema. Seven days after application, the lower part of the burn was completely healed whereas inflammation persisted in the upper area.

Example 53.-Skin graft of third degree burn A 30 year old man with a combination second and third degree thermal burn below his knee bilaterally was examined. 50% aqueous dimethyl sulfoxide in 15 cc. dosage was applied to both lower limbs (with a cotton swab). This dosage was applied as often as every three to four hours for ten days with relief of pain without the need of narcotics. Two days after the burn the patient was able to mobilize and institute physiotherapy. Ten days following the burn he was taken to the operating room and the eschar removed with a dermastome. The granulating bed under the skin appeared more luxuriant than normal. A culture was taken which revealed no growth. Two days later this patient came down with an infection involving Pseudomonas and Staph aureus under the skin grafts. Systematic antibiotics were given with control of the Staph but not of the Pseudomonas. Dimethyl sulfoxide was then applied and within 48 hours the Pseudomonas infections was under control. Healing of grafted skin was more rapid than usual. The dimethyl sulfoxide treatment was observed to enhance the repair associated with skin graft. One month later there was no evidence of the customary contracture.

Example 54.Radiation burn A 68 year old man with a 6 year history of a local irradiation burn to the skin of the left ankle caused by X-ray radiation was treated. On examination, the patient showed a typical radiation dermatitis with a nonhealing ulcer. 15 cc. of 100% dimethyl sulfoxide BID was started. Within ten days the ulcer was healed and the telangiectasia and atrophy of skin were less prominent.

RELIEF OF SIGNS AND SYMPTOMS OF RESPIRATORY DISTRESS In referring to respiratory distress, reference is intended to those infiammations and signs and symptoms associated with the nasal passages, sinuses, chest congestions, and immediately adjacent areas. The immediately adjacent areas include the nose and eyes, which usually exhibit characteristic signs of such distress and also the skin of the chest.

The membranes of the respiratory tract are susceptible to various infections and antigens which may result in the appearance of various signs and symptoms associated with different afflictions of recognized types. Such signs may include edema or swelling of mucous membranes, discharge, erythema or redness in the immediate area of the eyes and nose, as well as symptoms of discomfort such as nasal congestion and the like. Some or all of these signs and symptoms are seen in the upper respiratory distress known as coryza or the common cold, allergic rhinitis, and sinusitis. The common cold or coryza includes distress to nasal passages, sometimes the sinuses, and often the nose as shown by nasal discharge, redness and lacrimation. The sinuses are involved in the various inflammations of the sinuses collectively referred to as sinusitis. Upper respiratory distress may sometimes include severe signs such as suppurative or pus forming complications such as in paranasal sinusitis. A distress such as allergic rhinitis affects the nasal mucosa and it is due to pollens, to non antigenic irritants, and even in some cases to neurogemc psychosomatic causes. A particular form of allergic rhinitis is hay fever. Sinusitis may have different ori ins but generally includes inflammation of the sinuses along with the signs and symptoms described.

By contacting dimethyl sulfoxide compositions with tissue associated with or adjacent to sites of respiratory distress, relief of the signs and symptoms associated with such distress may be obtained.

It has been found that dimethyl sulfoxide compositions in a pharmaceutically acceptable form are very conveniently administered by applying a small volume directly to the nasal mucous membranes or by applying such compositions topically to the skin around the eyes or the nose. A given volume, which may only comprise a few cc. of dimethyl sulfoxide in concentrations anywhere from about in aqueous solutions to 100%, may be applied with a cotton swab applicator. It is preferred that the applied liquid dimethyl sulfoxide compositions leave the skin or nasal membranes wet. It may be required to repeat such application with a nasal spray, if necessary, until an effective amount is absorbed. This effective amount will be ascertained by the relief of the signs and symptoms associated with the particular respiratory distress.

It is of particular advantage to apply these compositions topically since it is easy and precludes any difficulty which might occur with more difiicult means of administration such as by injection. When applied to the dermal regions it is preferred to use a few cc. of a stronger concentration above 50% and as high as 100% dimethyl sulfoxide. When the compositions are applied to the nasal mucous membranes it is preferred to reduce the concentration to about 50% or below in water. Generally, compositions containing concentrations of at least about 10% dimethyl sulfoxide are effective topically to mucous membranes and at least about 50% to the skin in relieving the signs and symptoms of such respiratory distress.

The following examples are illustrative.

Example 55.-Coryza The common cold is an acute infection of the upper respiratory tract in which coryza, or, popularly, a cold in the head, is the most prominent feature. The characteristic signs and symptoms are sneezing, nasal obstruction, thin nasal discharge, a feeling of tightness in the nose and watery eyes. The signs noted are that the nasal mucosa is reddened and edematous while the nasal discharge is usually obvious.

A 32 year old white male subject had a 12 hour history of signs and symptoms consistent with the common cold. The major complaints were sneezing, obstruction of both nostrils, and a profuse thin nasal discharge. One cc. of 100% dimethyl sulfoxide in Water Was placed into each nostril with a medicine dropper. One hour after application the subject reported an ability to breathe normally through both nostrils and an absence of a thin nasal discharge. This relief lasted for six hours.

Examination of six subjects with coryza led to the conclusion that administration of dimethyl sulfoxide topically to the cutaneous region, associated with the signs and symptoms of a cold, leads to a shortened duration of the symptomatology in addition to obtaining rapid relief of signs and symptoms.

Example 56.Allergic rhinitis This upper respiratory distress is usually characterized by a sudden onset of sneezing, itching of the nose and lacrimation. Another sign is a characteristic pale, boggy appearance of the turbinates. A 28 year old white male subject had a sudden onset of sneezing, itching of the nose, lacrimation, as well as a previous history of these signs and symptoms. The mucous membranes over the bones situated on the outside of the nasal fossae, were pale and boggy. Dimethyl sulfoxide was applied in a volume of 0.75 cc. in a aqueous solution. This composition was applied with an applicator stick into each nostril. There was no relief of signs and symptoms during the first half hour, but at the end of one hour, examina- 22 tion of the nasal mucosa revealed less edema and less bogginess. The itching and lacrimation also disappeared at this time.

Example 57.-Sinusitis Infiammations of the nasal accessory sinuses are closely related to rhinitis. Nearly always, acute inflammatory involvement of the nasal cavities precedes and leads to chronic infection and inflammation of the air sinuses by obstructing the drainage orifices of the sinuses.

The early phases of an acute sinusitis show edema of the lining epithelium which may completely obstruct the drainage orifice of the sinuses and, eventually, secondary bacterial infection which may cause frank suppuration or formation of pus to replace the watery discharge.

Chronic bacterial infection may give rise to lacerations and progressive fibrosis of the subepithelial connective tissue. During the early stages, the mucous membranes of the sinuses and nose are thickened, edematous, and pale grey to red depending upon the degree of hyperemia.

The nasal cavities are narrow and turbinates or nasal bones are enlarged due to thickened mucous membranes. The mucosal surfaces of the nose are covered by a thin watery to mucoid discharge which is relatively clear. In chronic sinusitis, congestion, engorgement, edema and enlargement of the turbinates is heightened.

A white female subject had maxillary sinusitis. Two cc. of dimethyl sulfoxide was topically applied to the cutaneous region over the maxillary sinus. Within two hours after application, there was a heavy mucous discharge and a diminution of symptoms. This subject had no further difliculty. Reapplication was not necessary with this subject, although with other subjects several repeated applications were required.

Example 58.--Si.nusitis A 62 year old female subject had a left ended maxillary sinusitis. Three cc. of 100% dimethyl sulfoxide was applied topically over the cutaneous region of the involved area. Within two hours after application, the congestion was relieved and there was no recurrence within three months, which was the last time the subject was examined.

Example S9.Si.nusitis A 63 year old nurse had acute sinusitis of three days duration. Two cc. of 100% dimethyl sulfoxide was applied topically over the cutaneous regions of the maxillary and frontal sinuses. One half cc. of 50% dimethyl sulfoxide was applied topically within each nasal cavity. Symptoms and signs disappeared within two hours after application, and congestion and enlargement of the turbinates diminished.

Example 60.Chronic sinusitis Chronic paranasal sinusitis usually follows neglected or inadequately treated episodes of acute sinusitis and results from the continued operation of the same predisposing factors. Chronic infection exhibits the local symptoms and signs of nasal obstruction, nasal discharge, headache, cough and recurring colds. The recurrent preenting symptom of chronic paranasal sinusitis is persistent nasal obstruction which may be unilateral or bilateral. Nasal and post nasal discharges invariably accompany the chronic sinus infection. Recurrent or constant headache is observed.

A 42 year old female had a 15 year history of chronic sinusitis. She had bilateral nasal obstruction and recurrent headaches. The nasal obstruction was most prominent in the left nostril. The signs of marked edema and pale nasal mucosa were seen upon examination. One cc. of 100% dimethyl sulfoxide was placed into each nostril by applying the composition topically to the nasal membrane. One cc. of 100% dimethyl sulfoxide was additionally applied topically to the skin over both maxillary and frontal sinuses. The total dose used was 6 cc. of 100% dimethy sulfoxide, one cc. dermally over each of the four sinuses and 1 cc. in each of the nasal cavities. Two hours after application, examination showed that the signs of edema were markedly reduced and the subject reported that breathing was now normal. Symptoms recurred in a mild form, particularly nasal obstructions on the day following application. Dimethyl sulfoxide in the same dosage schedule was reapplied to the subject and complete relief of the nasal obstruction occurred. This relief lasted for about three weeks.

Example 61.Respiratory congestion Respiratory congestion involves tenacious mucus in the bronchial tree and is characterized by nonproductive cough, that is, a cough which does not dislodge the mucus so it can be expectorated.

Three subjects were treated for respiratory congestion by topical application of 50% by volume dimethyl sulfoxide in 50/50 v./v. ethanol and glycerine to the chest and anterior neck. The dimethyl sulfoxide in each instance was applied to the skin in an amount sufficient to wet it thoroughly, for a total amount of about 6 cc. for each subject. In each case, a productive cough resulted and definite congestion relief was noted. The first evidence of relief appearing in about to minutes after application.

It is believed that the mechanism of action involved is that of a expectorant.

Example 62.--Expectorant The term, expectorant, refers to reduction of the acute inflammation and stimulation of protective secretion. A 75 year old male subject had a chronic pulmonary condition with a nonproductive cough. He was given a topical application of 15 cc. of 100% dimethyl sulfoxide daily to his entire left lower extremity to treat arteriosclerotic ulcerations. Fifteen minutes after application, the dry cough became productive, that is, protective mucus began to secrete and to be expectorated. The mucus les sened the paroxysms of coughing and seemed to render the cough more effective. The paroxysms of duration of benefit with a single application was approximately six hours.

RELIEF OF SIGNS AND SYMPTOMS OF ARTHRITIS Arthritis is a term generally used to denote joint disorders and this term is particularly applied to disorders of joints which are inflamed. Among the signs which may appear are limitations of motion, deformity and crepitation, which is a grating feeling or noise resulting from the rubbing together of opposing joint surfaces. Swelling is also a sign which is frequently observed and this may be caused by accumulation within the joint space of a fluid, subcutaneous edema, localized effusion or bony enlargement. The reported symptoms are usually pain and stiffness. These signs and symptoms are frequently associated with great discomfort and in some cases immobility.

There are certain recognized classes of arthritis which may differ somewhat in their signs and symptoms, or may have a different etiology, or origin. In any event, the foregoing symptoms and signs are usually found in these classes of arthritis and administration of dimethyl sulfoxide leads to the relief thereof. As previously discussed, lrelief is intended to mean either an observable or reported reduction, or elimination of some or all signs and symptoms. The topical route is preferred in treatment of this disorder, the composition being liberally painted on the skin surrounding the affected joint. However, injections, particularly interarticular, may also be called for. For more chronic situations particularly in the case of rheumatoid arthritis, a prolonged regimen, extending for a number of weeks, may be required before measurable relief is seen.

The following examples are illustrative.

24 Example 63.Relief of symptoms and signs of rheumatoid arthritis Rheumatoid arthritis is a disease which tends to be chronic and to result in characteristic deformities. One sign is inflammation which is present together with the symptomatology of stiffness and pain. Other signs are thickening of the synovial membrane, the destruction of cartilage and bone, and ankylosis. The latter term designates abnormal immobility (or consolidation or fixation) of a joint. The joints of a hand are usually involved and muscle symptoms such as aching, tenderness and stiffness occur early and are usually prominent throughout the course of the afiliction.

(A) A 36 year old white female subject reported symptoms of pain and swelling and showed signs of redness and deformity in the joints of the second and third fingers of the right hand, particularly the metacarpophalangeal joints. The measured girth with calipers of the involved joints was 8.75 cm. for each finger. There was limitation of motion in all directions. One cc. of dimethyl sulfoxide was applied with an applicator stick topically so that the wet liquid surrounded each of the involved joints. After one half hour, the subject could move both joints through a full range of motion without pain. One hour after treatment, actual measurement of the joint circumference revealed 8.25 cm. on one joint and 8.00 cm. on the other joint. The symptom of pain was relieved for 12 hours, at which time it was observed that the swelling remained diminished.

(B) A 42 year old female subject reported pain in the proximal interphalangeal joints of the first and second digits of the left hand. These are the middle joints in the first two fingers. Swelling, redness, heat and deformity were observed as signs. The circumference of the joint of the first digit was measured to be 6.25 cm. and the circumference of the proximal interphalangeal joint in the second finger was 6.75 cm. Dimethyl sulfoxide at 100% concentration was applied with an applicator stick in a volume of 1.2 cc. so that the liquid surrounded both involved joints. Five minutes after treatment, 1.2 cc. was again applied to each of the involved joints with an applicator stick in the same manner. Definite relief of symptoms did not occur until one hour after application when the subject was able to move both joints through a whole range of motion. Measurement of the joint at the end of one hour revealed no diminution in edema. The subject was observed again after 12 hours at which time measurement showed 5.75 cm. of the first finger and 6.00 cm. of the second finger. After an additional 12 hours the subject was still able to move both involved joints through a full range of motion and the duration or relief of symptoms and signs lasted 48 hours.

(C) A 6 year old female subject with cervical (affecting vertebrae of neck) rheumatoid arthritis, refractory to cortisone and salicylates, was treated by topical application with 100% dimethyl sulfoxide to the involved area. Prior to treatment, the subject was unable to move her head to the left of the midline without discomfort. One half hour later she was able to touch her chin to her left shoulder without pain, and the relief of this symptom lasted about twelve hours.

Example 64.Relief of symptoms and signs of osteoarthritis This afliiction occurs more commonly in older people and usually afflicts the weight bearing joints, and curiously, the distal interphalangeal joints of the finger, or the end joint. Some of the symptoms associated with this afiliction are pain and stiffness, and the pain is generally of a mild and aching type. The pain generally appears with exercise of a part and abates with rest. There may be no signs of joint enlargement although, when present, it is generally the result of secondary hypertrophy of bone. Signs of enlargement are hardness and knobbiness which is unlike the soft flocculent swelling in rheumatoid arthritis. There may be signs of tenderness but rarely warmth or erythema (redness of the skin), or subcutaneous nodules.

(A) A 60 year old white male subject had osteoarthritis of the right knee which diagnosis was consistent with X-ray and clinical findings. There was no sign of edema and the main sign was limitation of motion restricting extension of the knee joint by about 30 degrees. A total of cc. of 100% dimethyl sulfoxide was applied with an applicator stick topically to generously surround the involved joint. The solution was left on the skin and not wiped off. Five minutes after application, 3 cc. of 100% dimethyl sulfoxide was again applied in the same manner. Examination of the joint one hour after the last application showed that the patient could fully extend his leg. The relief of this sign lasted about 12 hours. This subject was treated daily for two weeks by applying a total of 8 cc. of 100% dimethyl sulfoxide topically with an applicator stick to the involved joint once per day. The liquid dimethyl sulfoxide was carefully and generously applied over a period of several minutes around the joint so that the skin over the joint was thoroughly wetted with care taken not to spill or lose any of the material. One week after all treatment was terminated, the subject could still extend the joint without pain.

(B) A 63 year old female subject with osteoarthritis of both knees for years was treated. The subject could not extend both knees the last 30 degrees without pain. 100% dimethyl sulfoxide was liberally applied to the right knee so that the area remained wet. Forty-five minutes after treatment, the subject could completely extend her right knee Without pain. The left knee remained unchanged. The relief of the symptoms of pain in the right knee lasted about twelve hours.

(C) A 4 year old thoroughbred gelding had chronic osteoarthritis of the right ankle for approximately 18 months. The horse was raced infrequently because of the difficulty of maintaining soundness following the race.

Dimethyl sulfoxide at 100% was applied daily topically with a brush to the right ankle and placed under a band age. After four days application it was noted that there was a marked improvement in the animals movement and the animal was worked out on the race track A; of a mile. Following this workout the animal was seen to walk normally. The medication was continued two more days and the animal was worked out of a mile and again returned to the stable in sound condition. A marked elfect on the animals pain was noted as well as an antiinflammatory response.

Example 65.Relief of signs and symptoms of gouty arthritis Gouty arthritis includes a deposit of sodium urate crystals and some of the signs are inflammation and degenerative reactions. The changes occur chiefly in joints or bones, bursae, and cartilagenous structures. Any or all joints may be involved, although usually those of the lower extremities chiefly the great toes, have the greatest incidences. The first sign. in most cases, is acute arthritis and metatarso-phalangeal joint of the great toe is frequently the first joint involved. Classically, the signs include swollen joints, tenderness to touch, and a cyanotic, violaceous color of the skin. The symptom is excruciating pain.

(A) A 62 year old white male subject had a four hour history consistent with the gout of the metatarso-phalangeal joint of the left great toe. He had recurring bouts of gout misery in the 5 years prior to examination. The observable signs include an edematous great toe joint measuring 10.00 cm. in girth by caliper and being markedly tender to palpation. It also had a purple color. Two cc. of dimethyl sulfoxide of 100% strength were applied locally surrounding the entire joint and part of the anterior foot. This was reapplied in a volume of 1 cc. of 100% dimethyl sulfoxide five minutes later. One half hour after the last application, the symptom of pain had subsided and the joint measured 9.75 cm. This relief of the symptom of pain lasted about 12 hours at which time the pain returned. At that time, the joint measured 9.5 cm. in circumference Two cc. of dimethyl sulfoxide was reapplied and the same relief by diminution of edema was observed. The relief of edema. was shown by circumferential measurement four hours after the second treatment, which was 9.25 cm. Only 2 applications were necessary and all symptoms and signs disappeared thirty-six hours after the initial treatment.

(B) A 72 year old white subject had typical gout of the metatarsophalangeal joint of the left great toe. The observed signs were tenderness to touch and swelling. The joint measured 10.5 cm. in girth by caliper. 100% dimethyl sulfoxide was applied topically in a volume of 2 cc. to surround the joint. Five minutes after application, 2 cc. of 100% dimethyl sulfoxide was again applied by surrounding the joint. One hour after the last application, the symptom of pain diminished to about 25% of what it was prior to treatment and the sign of swelling was reduced as shown by a joint measurement of 10.0 cm. in girth. Twelve hours later the symptom of pain was still absent and the sign, of swelling diminished further as shown by a joint measurement of 9.5 cm. in girth. Two cc. of 100% dimethyl sulfoxide was reapplied over the next 2 days in 3 separate treatments in the same manner as before. Seventy-two hours after onset of the gout, all symptoms and signs had completely disappeared.

(C) A 65 year old male subject with acute gouty arthritis of the right first metacarpo-phalangeal joint was examined. The signs observed in the area were inflammation and tenderness to touch as well as complete limitation of painless motion. 100% dimethyl sulfoxide was applied topically in liberal amounts so that the area was wetted. Thirty minutes after application, the sign of edema subsided and the subject was able to move the involved joint, and a full range of motions was obtained. The relief from the symptom of pain lasted for 12 hours.

RELIEF OF EMOTIONAL OVERACTIVITY AND MENTAL DEPRESSION It is desirable to relieve emotional over-activity of humans which in both neurotic and psychotic states may take the form of anxiety tensions, loss of emotional control and equilibrium, and like signs which may collectively be termed herein as emotional overactivity. It is also desirable to relieve mental depression which also often occurs in mental disorders. A recognized class of drugs has been developed including the widely used chlorpromazine and the meprobamates. These drugs are characterized by reducing the overactivity or lessening emotional excesses and anxiety tensions and the like and by exerting an antidepressant effect on anergic individuals, particularly in neurotic and pyschotic disorders. It is a characteristic of these drugs that they attain the desirable properties without unduly depressing the central nervous system or the consciousness or alertness of the subject. This class of drugs has frequently been referred to as tranquilizers, or ataraxics.

Similarly, dimethyl sulfoxide has a tranquilizing or ataractic effect in the same sense of reducing emotional overactivity and in relieving mental depression in subjects sulfering from mental disorders. It is particularly useful in treating psychotic or severe neurotic symptoms and particularly acute schizophrenic or anxiety states.

The particular amount of dimethyl sulfoxide to be administered to reduce emotional overacti-vity or depression will understandably be determined by the expertise of the attending practitioner. A great degree of emotional overactivity or depression will normally urge the practitioner to administer higher concentrations of dimethyl sulfoxide in greater amounts, more repeatedly, say an amount to obtain a daily dosage of 15 to 20 cc. of dimethyl sulfoxide.

An effect, however, may often be obtained by only one or two treatments of only a few cc. of dimethyl sulfoxide compositions containing anywhere from about 25% to 100% of the compound.

Dimethyl sulfoxide may be administered by the different oral and injectable routes, and it may be applied topically to a cutaneous region all as discussed previously. This may be done by applying a small volume such as 2 to 5 cc. of a composition containing at least about 50% dimethyl sulfoxide and repeating the dosage as necessary.

Topical application to cutaneous regions such as the skin and mucous membranes will lead to absorption so the vascular system will carry the compound to the central nervous system where the tranquilizing effect will occur. It is a unique advantage that dimethyl sulfoxide penetrates or is absorbed in a surprising manner through the cutaneous regions.

The following examples are illustrative.

Example 66 A 48 year old female subject under the care of a psychiatrist was observed to exhibit signs of anxiety tension and nervousness. An application of 6 cc. of 100% dimethyl sulfoxide was made to her lumbosacral back. About one hour after application, the subject was observed to be relaxed and less anxious. Only minimal drowsiness was reported.

COMPOSITION AND DOSAGE FORMS The type of composition and dosage form desirable will, of course depend upon the route of administration and the examples which follow are illustrative. Dosage forms to obtain the appropriate dosage in accordance with the foregoing teaching may easily be determined by considering concentration and volume.

In general, the concentration of dimethyl sulfoxide may vary from as low as 1% to as high as 100%. Dimethyl sulfoxide preferably is diluted with pharmaceutically acceptable diluents. It is freely miscible with water, ethanol, glycerin and other solvents. As will be described below, particularly advantageous results may be obtained by diluting dimethyl sulfoxide with a pharmaceutically acceptable miscible liquid, especially water or glycerin and including ethanol and saline solution, to form liquid, semisolid and solid formulations containing specified ranges of dimethyl sulfoxide concentration.

As will be discussed in detail pharmaceutical excipients may be employed to form advantageous dosage forms of dimethyl sulfoxide and additionally, adjuvants may be incorporated in such formulations where it is desired to combine the effects of dimethyl sulfoxide with another pharmaceutical.

However, whatever the formulation, it is required that the dimethyl sulfoxide be applied in a pharmaceutically acceptable form, by which is meant that it be sufficiently purified so that it does not cause any untoward reaction or injury to the body of the subject from contaminants and the like,

For injection, concentration of dimethyl sulfoxide from 1% to 20% are particularly suitable. For intravenous administration, the lower concentrations of between 1% and 5% may be preferred and for subcutaneous, intramuscular, and intraperitoneal injections, the concentration range of 10% to may be preferred. For some types of injections, such as intraarticular, even higher concentrations say up to 40% may be suitable. It has been found highly desirable, particularly for larger doses, in order to render such injection solutions more physiologic and minimize hemolysis which may otherwise be caused by dimethyl sulfoxide, to make the solutions saline by the addition for example of sodium bromide, sodium iodide, disodium hydrogen phosphate, sodium citrate, sodium carbonate, sodium salicylate, potassium bromide, calcium levulinate, calcium chloride, calcium gluconate, and magnesium sulfate, dextrose, urea, lactose and galactose, and

other well-known equivalent agents for this purpose. Preferably an amount is added to make the solution isotonic, as for example 0.9% sodium chloride, 1.19% potassium bromide, 9.39% dextrose, etc. Such injection compositions are illustrated by the 1%, 5%, 10% and 20% dimethyl sulfoxide formulations in following Example 68. Such diluted forms may also find better patient acceptability for oral administration, perhaps with an excipient to improve the taste.

For application to the intact skin, 100% strength dimethyl sulfoxide may be employed. However, compositions containing at least about 50% dimethyl sulfoxide along with a minor amount of a pharmaceutically acceptable diluent, such as water, alcohol or glycerol, has been found to be uniquely suitable for skin application. A concentration of at least about 50% dimethyl sulfoxide has been found necessary to efficient, practical penetration of the skin barrier. Lower concentrations for this unique route may thus result in less than the desired effect. On the other hand, with very high concentrations of dimethyl sulfoxide, as those substantially above 90%, the undesired side effects of local skin irritation, erethyma and urticaria increase markedly while no substantial increased benefit is obtained. Thus, we have found that for dermal application, by diluting the dimethyl sulfoxide with an appropriate diluent, particularly to a concentration of 90% or less, these side effects can be minimized and patient acceptability thereby enhanced consistent with effective results. Therefore, for the highly advantageous administration of dimethyl sulfoxide to the intact skin for its effect on deeper tissue, due to its unusual penetration properties, compositions containing from about 50% to about 90% dimethyl sulfoxide and a pharmaceutical diluent, as exemplified by the 50%, and aqueous dimethyl sulfoxide compositions of following Example 68, have been found uniquely suitable and desirable. Dimethyl sulfoxide-glycerin solutions of 10% to 40% glycerin content are quite advantageous to minimize skin irritation due both to the dilution of the dimethyl sulfoxide and the emollient effect of the glycerin, which tends to soothe the irritation and skin dryness which may be caused by the dimethyl sulfoxide.

For topical application to the mucous membranes of the body, as for example the mouth and throat, nasal passages, eyes, bladder, anal, urethral, and vaginal regions, compositions including dimethyl sulfoxide at a concentration of at least about 10%, preferably 20% to 40%, and including a pharmaceutical diluent, as for example water, alcohol or glycerol, are especially suitable, although lower concentrations of dimethyl sulfoxide say down to 3% by weight, may be useful in some instances. Dilution of the dimethyl sulfoxide to a concentration of 90% and below is also advantageous in minimizing irritation to the tissues. Thus 10% to 90% water solutions of dimethyl sulfoxide are particularly suitable.

For the various topical routes, dimethyl sulfoxide may be formulated into highly convenient dosage forms as illustrated in the examples which follow. Such forms include solutions (paints), nasal sprays, lotions, ointments (including creams and gels), suppositories and the like.

The solutions and nasal sprays may simply contain dimethyl sulfoxide and amounts of water, glycerin or other diluents as previously discussed. Isotonic saline may be preferable as a diluent for nasal sprays or other mucous membrane applications.

Lotions, ointments and suppositories may be formed by incorporating with the dimethyl sulfoxide various gelling agents or other thickener-s (viscosity increasers) which permit release of the dimethyl sulfoxide to the skin or mucous membrane upon application. Thes forms are advantageously employed to lessen the runoff from the skin that may occur with the more fluid composition forms, thereby permitting greater mobility for the patient immediately following treatment. They also permit more sustained contact of the dimethyl sulfoxide with the treated surfaces. Such lotions, ointments and suppositories may contain the usual ingredients to provide a base, as for example a fatty alcohol such as cetyl alcohol, an emulsifier such as lauryl sulfate and water. Another base may be formulated by combining equal weight amounts of stearic acid, cetyl alcohol, triethanolamine and glycerol monostearate together with water. Still other bases may utilize polyethylene glycols of different viscosities, depending upon the desired consistency and concentration of dimethyl sulfoxide to be incorporated. Dimethyl sulfoxide may be added to the lotion, ointment or suppository base in varying amounts as desired, generally up to 50% or higher depending on the consistency desired.

A suppository form is highly advantageous, particularly for the treatment of hemorrhoids. The usual low melting gelling agents may be employed for this purpose. The dimethyl sulfoxide concentration is usually 20% or below in this form but it may be higher depending upon the strength of the gelling agent. Concentrations of 3% and 20% are generally satisfactory. Gelling agents such as polyethylene glycols of varying yiscosities, glycerol monostearate and the like may be employed. A high viscosity polyethylene glycol, such as polyethylene glycol 4000, water and 20% dimethyl sulfoxide may be a suitable formulation. By using lower viscosity gelling agents of the same type a satisfactory ointment may be made which may be smeared on the involved area to achieve similar results.

The liquid pharmaceutical dosages may be provided and dispensed in graduated containers or containers containing a given volume such as, for example, 1 cc., 2 cc., 5 cc., cc., cc., 100 cc., 200 cc., or 500 cc. The containers with volumes of 20 cc. and above provide convenient multiple dosage forms and those containing a typical single dose, say from 0.5 gram to 20 grams of dimethyl sulfoxide, provide convenient unit dose forms. This may be in a breakable or openable capsule or ampule (for injectables). The practitioner need only open and dispense all or a determined part to a subject. In this way, the dosage may be ascertained and controlled readily by the practitioner. Nasal spray bottles, aspirators, squeeze tubes (for lotions and ointments) and cotton stick applicators may all be utilized for topical application.

Example 67.-Compositions of determined amounts Dimethyl sulfoxide is distilled at reduced pressure of under mm. Hg in order to keep the temperature at 90 or less, and thereby prevent deterioration. A rapid distillation at 16 mm. Hg and 79 C. head temperature is satisfactory. An inert gas such as nitrogen is preferably used in the distillation process to displace other gases which may adversely affect the purity of the compound. The distilled liquid is filtered through activated charcoal and again distilled. The collected dimethyl sulfoxide is in a pharmaceutically acceptable form, and is transferred to cleaned bottle containers of 100, 200, and 500 ml. volumes. The bottles are stoppered with cleaned closures and identified. Other pharmaceutically purified 100% dimethyl sulfoxide volumes are transferred to 200 cc. bottles graduated to one cc. units, stoppered with cleaned closures and identified. Another volume of 100% dimethyl sulfoxide is transferred to a cleaned 100 cc. bottle and stoppered with a closure filled with a suction bulb and a 10 cc. tube graduated to one cc. units.

Another volume of 100% dimethyl sulfoxide is Berkfield filtered to obtain a sterile form which is transferred to a series of 2 cc., 5 cc., and 10 cc. ampules which are then heat sealed to provide a form for injection, preferably after dilution with sterile, pyrogen-free diluent. The sterile ampules are checked for pyrogens with standard rabbit tests. These ampules represent amounts for administration (dosages) of about 2, 5, and 10 grams of dimethyl sulfoxide, respectively.

Example 68.Pharmaceutical solutions of dimethyl sulfoxide One hundred percent dimethyl sulfoxide in a pharmaceutically purified form is collected as shown in Example 67. Dilutions are made with distilled water and transferred to 500 cc. cleaned bottles: which are then stoppered with cleaned closures. The dilutions provide separately bottled solutions containing dimethyl sulfoxide at concentrations of 1%, 5%, 10%, 20%, 50%, 75%, and The bottles are identified and are available for topical or oral application.

Solutions of similar concentrations are also prepared using 0.9% saline (sodium chloride) as the diluent, in order to render the solutions isotonic.

The distilled water and saline solutions containing dimethyl sulfoxide at concentrations of 1%, 5%, 10% and 20% are Berkfield filtered to Obtain a sterile form which is placed in 5 cc., 10 cc. and 20 cc. ampules, as well as cc. bottle containers. The ampules are heat sealed and the bottles are stoppered. The sterilized solutions are checked for pyrogens with standard rabbit tests. These compositions are available for injection or for administration to open wounds, burns, ulcers or the like wherein there is a possibility of infection. They represent amounts for administration (dosages) of from about 0.05 gram of dimethyl sulfoxide, in the case of 5 cc. ampules at 1% concentration of dimethyl sulfoxide to about 20 grams, in the case of 100 cc. bottles at 20% concentration of dimethyl sulfoxide.

Example 69.Ointment and suppository compositions Suppository and ointment compositions, suitable for rectal, urethral or vaginal use, may 'be prepared with the following formulations:

Suppository (dimethyl sulfoxide concentration-40% Percent Dimethyl sulfoxide 10 Water 10 Carbowax polyethylene glycol 1540 30 Carbowax polyethylene glycol 1000 1 50 Suppository (dimethyl sulfoxide concentration-12%):

Carbowax polyethylene glycol 4000 88 Dimethyl sulfoxide 12 Suppository (dimethyl sulfoxide concentration-10% Carbowax polyethylene glycol 4000 84 Dimethyl sulfoxide 10 Glycerin 6 Carbowax is a proprietary name of Union Carbide and the number following is an arbitrary designation related to the viscosity and melting point of the polyethylene glycol, the higher the number the higher the melt point and viscosity. For ointments, the compositions are desirably adjusted for a lower viscosity. Other gelling agents such as glycerol monostearate and cocoa butter may be used. They should be selected to melt at body temperature and release the dimethyl sulfoxide. The concentration of dimethyl sulfoxide preferably maybe between 3 and 20%. Higher concentrations of 50% and above may also be employed if the gelling agent can gel a higher quantity.

The gelling agents may be melted in a water bath, the dimethyl sulfoxide and any other active ingredients added with mixing. The mix may be cooled to 50 C. and poured into suppository molds to form the product.

Example 70.fiSuppository composition The following ingredients are combined and the mixture is formed into a suppository which contains dimethyl sulfoxide at a concentration of about Carbowax-500 gms. Water50 cc. Dimethyl sulfoxide-100 cc.

Example 71 .Ointment composition The following ingredients are combined into an ointment form which contains dimethyl sulfoxide at a concentration of 45%.

Gms.

Carbowax 4000 675 Dimethyl sulfoxide (100%) 675 Isotonic Saline 150 Example 72.Lotion composition Acid mantle lotion base is a buflered aluminum acetate in a water miscible base supplied by the Dome Chemical Company of New York. A dimethyl sulfoxide cream was made as follows:

Acid mantle cream base-75 gms. Dimethyl sulfoxide (100% cc.

Example 73.Cream composition Acid mantle cream has is also a buffered aluminum acetate in a water miscible base suppled by Dome Chemical Company of New York. A 20% dimethyl sulfoxide cream was made as follows:

Gms. Acid mantle cream base 80 Dimethyl sulfoxide (100%) 20 Example 74.Compositions for topical treatment Particularly for topical treatment of first and second degree burns, water solutions of dimethyl sulfoxide from 20% to 90% dimethyl sulfoxide may be made by mixing dimethyl sulfoxide with an appropriate proportion of distilled water. Concentrations above 50% are most effective. Similarly, dilutions with glycerin may be prepared by proportional mixing to obtain compositions with 10% to 40% glycerin.

Example 75.-Nasal spray composition A 50% dimethyl sulfoxide solution in isotonic saline is transferred to a 50 cc. resilient plastic bottle and a closure with spray orifice is aflixed. A nasal spray is produced by flexing and releasing the side walls of the bottle. This bottle represents, in terms of weight, an amount for administration equivalent to about 25 grams of dimethyl sulfoxide.

A propellent nasal spray is also compounded by mixing water, 100% dimethyl sulfoxide and a sufficient amount of Freons to provide a propellent force. The concentration of the dimethyl sulfoxide in this form is about 25%.

The foregoing invention can now be practiced by those skilled in the art. Such skilled persons will know that the invention is not necessarily restricted to the particular embodiments presented herein. The scope of the in- Vention is to be defined by the terms of the following claims as given meaning by the preceding description.

We claim:

1. A method of relieving the signs and symptoms of tissue inflammation which comprises administering to a human or animal subject suflering from tissue inflammation an amount of dimethyl sulfoxide eflective for relieving signs and symptoms of tissue inflammation.

2. A method as in claim 1 and wherein the amount of dimethyl sulfoxide administered is between about 0.01 and 1.0 gram per kg. body weight per day.

3. A method as in claim 1 and wherein the dimethyl sulfoxide is applied directly adjacent to the area involved with tissue inflammation.

4. A method as in claim 1 and wherein the dimethyl sulfoxide is applied topically to a cutaneous region in proximity to the involved area in the form of a composition comprising dimethyl sulfoxide at a concentration of at least about by weight of the composition and a pharmaceutically acceptable diluent.

5. A method as in claim 1 and wherein the dimethyl sulfoxide is applied topically to a mucous membrane in the form of a composition comprising dimethyl sulfoxide at a concentration of at least about 3% by weight of the composition and a pharmaceutically acceptable diluent.

6. A method as in claim 1 and wherein said tissue inflammation is caused by a musculoskeletal injury.

7. A method of relieving pain which comprises administering to a human or animal subject suffering from pain an amount of dimethyl sulfoxide effective to relieve pain.

8. A method as in claim 7 and wherein the amount of dimethyl sulfoxide administered is between about 0.01 and 1.0 gram per kg. body weight per day.

9. A method as in claim 7 and wherein the dimethyl sulfoxide is applied topically to a cutaneous region in proximity to the area involved with pain in the form of a composition comprising dimethyl sulfoxide at a concentration of at least about 50% by weight of the composition and a pharmaceutically acceptable diluent.

10. A method as in claim 7 and wherein the dimethyl sulfoxide is applied topically to a mucous membrane in the form of a composition comprising dimethyl sulfoxide at a concentration of at least about 3% by weight of the composition and a pharmaceutically acceptable diluent.

11. A method of promoting muscle relaxation in a human or animal subject suifering from abnormal muscle contractions which comprises administering to the subject an amount of dimethyl sulfoxide effective to promote muscle relaxation.

12. A method as in claim 11 and wherein the amount of dimethyl sulfoxide administered is between about 0.01 and 1.0 gram per kg. body weight.

13. A method as in claim 11 and wherein the involved muscles are skeletal muscles and the dimethyl sulfoxide is applied topically to a dermal region in proximity to said involved muscle in the form of a composition comprising dimethyl sulfoxide at a concentration of at least about 50% by weight of the composition and a pharmaceutically acceptable diluent.

14. A method of relieving symptoms of vascular insufficiency in the blood and lymph circulatory system of a human or animal subject sufifering therefrom which comprises administering to said subject an amount of dimethyl sulfoxide effective to relieve symptoms of vascular insufliciency.

15. A method as in claim 14 and wherein the amount of dimethyl sulfoxide administered is between about 0.01 and 1.0 gram per kg. body Weight per day.

16. A method as in claim 14 and wherein said vascular insufliciency comprises a disorder involving the peripheral blood vessels.

17. A method as in claim 16 and wherein the dimethyl sulfoxide is applied topically to a cutaneous region in proximity to the involved vessels in the form of a composition comprising dimethyl sulfoxide at a concentration of at least about 50% by weight of the composition and a pharmaceutically acceptable diluent.

18. A method of relieving the signs and symptoms of a burn in a human or animal subject which comprises administering directly to the involved area an amount of dimethyl sulfoxide effective to relieve signs and symptoms of the burn.

19. A method of promoting the taking of a skin graft in a human or animal subject which comprises contacting the skin graft area following the transplant with an amount of dimethyl sulfoxide effective to promote healing of the graft.

20. A method of relieving the signs and symptoms of respiratory distress which com-prises directly contacting tissue associated with or adjacent to a site of respiratory distress in a human or animal subject suffering therefrom an amount of dimethyl sulfoxide effective to relieve signs and symptoms of respiratory distress.

21. A method as in claim 20 and wherein the amount of dimethyl sulfoxide administered is between about 0.01 and 1.0 gram per kg. body weight per day.

22. A method as in claim 20 and wherein the respiratory distress comprises distress of the upper respiratory tract and wherein the dimethyl sulfoxide is applied topically to the mucous membranes of the nasal passages or the oral cavity in the form of a composition comprising dimethyl sulfoxide at a concentration of at least about 3% by weight and a pharmaceutically acceptable diluent.

23. A method of relieving signs and symptoms of arthritis which comprises administering to a human or animal subject having a joint with arthritic signs or symptoms an amount of dimethyl sulfoxide effective to relieve signs and symptoms of arthritis.

24. A method as in claim 23 and wherein the amount of dimethyl sulfoxide administered is between about 0.01 and 1.0 gram per kg. body weight per day.

25. A method as in claim 23 and wherein the dimethyl sulfoxide is applied topically to the cutaneous region in proximity to the arthritic joint in the form of a composition comprising dimethyl sulfoxide at a concentration of at least about 50% by weight and a pharmaceutically acceptable diluent.

26. A method for promoting tissue repair in a human or animal subject suifering from tissue damage which comprises administering to the subject an amount of dimethyl sulfoxide elfective for promoting tissue repair.

27. A method as in claim 26 and wherein the amount of dimethyl sulfoxide administered is between about 0.01 and 1.0 gram per kg. body weight per day.

28. A method as in claim 26 and wherein the dimethyl sulfoxide is applied directly adjacent to the area involved with tissue damage.

29. A method as in claim 26 and wherein the dimethyl sulfoxide is applied to a cutaneous region in proximity to the involved area.

30. A method as in claim 29 and wherein the dimethyl sulfoxide is applied topically.

31. A method as in claim 30 and wherein the dimethyl sulfoxide is applied in the form of a composition comprising dimethyl sulfoxide at a concentration of at least about 50% by weight of the composition and a pharmaceutically acceptable diluent.

32. A method as in claim 31 and wherein said com position includes at least about 10% by weight of water.

33. A method as in claim 26 and wherein the dimethyl sulfoxide is applied topically to a mucous membrane.

34. A method as in claim 26 and wherein said tissue damage is caused by a non-living injurious stimulus.

35. A method as in claim 34 and wherein said tissue damage is a musculoskeletal injury.

36. A method as in claim 34 and wherein said injury is bursitis.

37. A method as in claim 1 and wherein said inflammation is caused by a non-living injurious stimulus.

References Cited UNITED STATES PATENTS 2,942,008 6/1960 Lubowe 252-364 3,044,936 7/1962 Achelis et a1. 424-337UX 3,067,096 12/1962 Trace et a1. 424337UX FOREIGN PATENTS 810,377 3/1959 Great Britain.

OTHER REFERENCES Faust: American Perfumer 77(1): 23-26 January 1962, Some New Components for Cosmetic and Dermatologic Vehicles.

Marson: Boll. Chimicofarm 102: 109-124 February 1963, Dimethyl Sulfoxide, a Water-Mimetic Solven Federal Register 33(176): 12776-42777, Sept. 10, 1968, Dimethyl Sulfoxide (DMSO) Preparations: Clinical Testing and Investigational Use.

SHEP K. ROSE, Primary Examiner 

